Benefit-Risk Considerations for Product Quality Assessments | Guideline Explorer

Description

This guidance describes the benefit-risk principles applied by FDA when conducting product quality-related assessments of chemistry, manufacturing, and controls (CMC) information submitted for FDA assessment as part of original new drug applications (NDAs) under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), original biologics license applications (BLAs) under section 351 of the Public Health Service Act (PHS Act), or supplements to such applications, in addition to other information (e.g., inspectional findings) available to FDA during its assessment.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

5

Biological Products

Requires analytical comparability per ICH Q5E

Combination Product

Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.

Parenteral Product

requires consideration of Class 1, 2A, and 3 elements

Biological Product

Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition

Small Molecule Drug Product

Drugs typically assessed for synthesis methods and impurities

Stakeholders

1

Interdisciplinary Team

Group including clinical, quality, and pharmacology assessors

Regulatory Context

Regulatory Activities

4

Preapproval Inspection

Inspection conducted before drug approval

NDA

New Drug Application

BLA

Biologics License Application

ANDA

Abbreviated New Drug Application

Document Types

2

Labeling

Cybersecurity information should be included in device labeling

Inspection Report

Information about facilities used during quality assessment

Attributes

5

Acceptable Quality

Standard for finished products

Quality Target Product Profile

QTPP impact should be considered in life cycle management.

Narrow Therapeutic Index

A drug characteristic that necessitates specific safety data considerations.

Shelf Life

Determined based on stability data; Established through stability testing; also called dating period.; Established through formal stability studies; Establishing the period during which a drug product is expected to remain within specifications; Period for drug products; The period during which a drug product is expected to remain within specifications; Duration product remains within acceptance criteria; Period during which product remains within specifications; Established for intermediates pu

Potency

Measurement of potency for biological products

Technical Details

Substances

2

Drug Substance

Postapproval changes to drug substances; the active pharmaceutical ingredient being modified; Evaluation of physical properties for drug substance; Active ingredient intended to furnish pharmacological activity; The molecule or ion responsible for the physiological or pharmacological action.; The active pharmaceutical ingredient subject to postapproval changes

Nitrosamine Contaminants

Impurities requiring additional testing

Testing Methods

2

Analytical Procedures

Used to examine samples for physical, chemical or biological changes

Stability Data

Documentation of stability data for drug products; Accelerated and long-term stability testing

Processes

3

CMC

chemistry, manufacturing, and controls

Sterilization

Required for contaminated equipment and media before disposal

Aseptic Processing

implied manufacturing process under QS regulation

Clinical Concepts

2

Adverse Events

Reporting adverse events when engaging with patients.; changes may be related to benefits, tolerability, and/or unintended effects

Pediatric Population

Frequently underrepresented in trials.

Identified Hazards

Hazards

4

Product Quality Issue

Risks posed by unresolved quality issues

Microbial Contaminants

Potential risk in biological product manufacturing

Mutagenic Impurities

DNA Reactive Impurities in Pharmaceuticals

Dose Dumping

Risk caused by failure of a drug's release mechanism

Standards & References

External Standards

1

Compendial Standards

Suitable reference standards include compendial standards

ICH References (4)

ICH Q9

Quality Risk Management recommended for combination products

ICH Q8(R2)

Pharmaceutical Development

ICH Q10

Pharmaceutical Quality System

ICH Q12

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management; referenced for established conditions and life cycle management tools; in line with recommendations described in ICH Q12; Guideline for technical and regulatory considerations for pharmaceutical product lifecycle management; Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.

Related CFR Sections (5)

21CFR314.3§ 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of the Federal Food, Drug, and Cosmetic Act apply to those terms when used in this part and part 320 of this chapter .Read full regulation →
21CFR314.50§ 314.50 Content and format of an NDA.
NDAs and supplements to approved NDAs are required to be submitted in the form and contain the information, as appropriate for the particular submission, required under this section. Three copies of the NDA are required: An archival copy, a review copy, and a field copy. An NDA for a new chemical enRead full regulation →
21CFR601.2§ 601.2 Applications for biologics licenses; procedures for filing.
(a) General. To obtain a biologics license under section 351 of the Public Health Service Act for any biological product, the manufacturer shall submit an application to the Director, Center for Biologics Evaluation and Research or the Director, Center for Drug Evaluation and Research (see mailing aRead full regulation →
21CFR314.102§ 314.102 Communications between FDA and applicants.
(a) General principles. During the course of reviewing an application or an abbreviated application, FDA shall communicate with applicants about scientific, medical, and procedural issues that arise during the review process. Such communication may take the form of telephone conversations, letters, Read full regulation →
21CFR314.81§ 314.81 Other postmarketing reports.
(a) Applicability. Each applicant shall make the reports for each of its approved applications and abbreviated applications required under this section and section 505(k) of the act.Read full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

95

Failure to establish adequate written procedures for production and process control

88

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

56

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

56

Failure to establish an adequate quality control unit

49

Failure to test samples of each component for identity and conformity

47

Failure to establish laboratory controls

35

Failure to thoroughly investigate any unexplained discrepancy

28

Failure to test samples of each component for identity

25

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics